Chronic infection in the airways is the most common cause of morbidity and mortality in cystic fibrosis. The link between CFTR mutations and infection remains uncertain. While many diverse hypotheses have been advanced, one point is clear: CF patients manifest some defect in host defense, and this defect is localized to the airway surface. Airway surface liquid (ASL) has antimicrobial properties that help keep the lungs sterile. The antimicrobial properties of ASL are enhanced when the salt conentration is low. This suggests that, regardless of the baseline salt concentrations in the ASL in vivo, further lowering it would improve antimicrobial activity. A strategy that could lower the salt concentration in the airways would be to apply a non-absorbable osmolyte to the ASL. This could reduce ASL NaCI concentration by substituting the osmotic effect of NaCI with a non-ionic osmolyte. Xylitol is a simple 5-carbon sugar, commonly used as a non-metabolizable sweetener. Xylitol has been shown to prevent or decrease the progression of dental caries and decrease the incidence of acute otitis media when used prophylactically. Our preliminary data are very encouraging: xylitol has low permeability across epithelia, it can reduce ASL salt concentrations, it does not inhibit ASL antimicrobial factors, and most importantly, xylitol can enhance ASL-mediated bacterial killing in vitro and in vivo. Our long-term hypothesis is that xylitol administration will prevent or delay the onset of CF airway infections. Towards that goal we propose to test the efficacy of xylitol in augmenting ASL killing in mice, sheep and adults with CF. We have 3 hypotheses. Administering xylitol to the airways will increase bacterial killing in mice. We will study the effect of xylitol on several CF bacterial pathogens administered to mouse lung. Aerosolized xylitol will prevent airway colonization/infection in large animals. We will ask if xylitol administration increases airway killing of a sheep airway pathogen M. haemolytica. Airway administration of xylitol is safe and reduces the bacterial burden in patients with CF. Xylitol has been given to humans intravenously and orally as a food additive. We will first ask if aerosolized xylitol is safe in normal volunteers and determine how long it stays in the ASL compartment. We will then ask if xylitol administration is safe in CF patients and whether it can decrease the bacterial burden in their lungs.